Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report

Singh P, Shah DA, Jouni M, Cejas RB, Crossman DK, Magdy T, Qiu S, Wang X, Zhou L, Sharafeldin N, Hageman L, McKenna DE, Armenian SH, Balis FM, Hawkins DS, Keller FG, Hudson MM, Neglia JP, Ritchey AK, Ginsberg JP, Landier W, Bhatia R, Burridge PW, Bhatia S. Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report. J Am Heart Assoc. 2023 Oct 3;12(19):e029954. doi: 10.1161/JAHA.123.029954. Epub 2023 Sep 26. PubMed PMID: 37750583; PubMed Central PMCID: PMC10727235.

Anthracycline‐induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood‐based mRNA expression profiles in anthracycline‐exposed childhood cancer survivors with and without cardiomyopathy. We designed a matched case‐control study (Children’s Oncology Group‐ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline‐exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human‐induced pluripotent stem cell‐derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty‐six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified “hepatic fibrosis” and “iron homeostasis” pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA‐knockout human‐induced pluripotent stem cell‐derived cardiomyocytes showed increased sensitivity to doxorubicin.